2002
`
`THE UNITED STATES PHARMACOPEIA
`USP 25
`
`NF 20
`THE NATIONAL FORMULARY
`
`By authority of the United States Pharmacopeial
`Convention, Ina, meeting at Washington, D. C,
`April 12—16, 2000. Prepared by the Council of Experts
`and published by the Board of Trustees
`
`Official from January I, 2002
`
`The designation on the cover of this publication, “USP NF
`2002,” is for ease of identification only. The publication
`contains two separate compendia: The Pharmacopeia of the
`United States Twenty—fifth Revision, and the National
`Formulary, Twentieth Edition.
`
`UNITED STATES PHARMACOPEIAL CONVENTION, INC.
`12601 Twinbrook Parkway, Rockville, MD 20852
`\\ _
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2020 Page 1
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2020 Page 1
`
`

`

`NOTICE AND WARNING
`
`Concerning US. Patent or Trademark Rights
`
`The inclusion in the Pharmacopeia or in the National Formulary ofa monograph on any drug in respect
`to which patent or trademark rights may exist shall not be deemed, and is not intended as, a grant of, or
`authority to exercise, any right or privilege protected by such patent or trademark. All such rights and
`privileges are vested in the patent or trademark owner, and no other person may exercise the same with-
`out express permission, authority, or license secured from such patent or trademark owner.
`
`Concerning Use of USP or NF Text
`
`Use ofthe USP-NF is subject to the terms and conditions of the USP-NF License Agreement. Attention
`is called to the fact that the USP-NF is fully copyrighted. Authors and others wishing to use portions of
`the text or images in any manner not expressly permitted by the License Agreement should request
`permission to do so fi'om the Secretary of the USPC Board of Trustees.
`
`Copyright © 2001 The United States Pharmacopeial Convention, Inc.
`12601 Twinbrook Parkway, Rockville, MD 20852
`All rights reserved.
`ISSN 0195-7996
`ISBN 1—889788-10-4
`Printed in Canada by Webcom Limited, Toronto, Ontario
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2020 Page 2
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2020 Page 2
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2020 Page 3
`
`

`

`1870
`
`(51) Antimicrobial—Effectiveness Testing / Microbiological Tests
`
`USP 25
`
`All useful antimicrobial agents are toxic substances. For maximum
`protection of patients, the concentration of the preservative shown to
`be effective in the final packaged product should be below a level that
`may be toxic to human beings.
`The concentration of an added antimicrobial preservative can be
`kept at a minimum if the active ingredients of the formulation possess
`an intrinsic antimicrobial activity. Antimicrobial effectiveness,
`whether inherent in the product or whether produced because of the
`addition of an antimicrobial preservative, must be demonstrated for
`all injections packaged in multiple-dose containers or for other pro-
`ducts containing antimicrobial preservatives. Antimicrobial effective-
`ness must be demonstrated for multiple-dose topical and oral dosage
`forms and for other dosage forms such as ophthalmic, otic, nasal, ir-
`igigatiqn, and dialysis fluids (see Pharmaceutical Dosage Farms
`1151 ).
`This chapter provides tests to demonstrate the effectiveness of anti—
`microbial protection. Added antimicrobial preservatives must be de-
`clared on the label. The tests and criteria for effectiveness apply to a
`product in the original, unopened container in which it was distribu—
`ted by the manufacturer.
`
`Change ta read:
`
`PRODUCT CATEGORIES
`
`For the purpose of testing, compendial articles have been divided
`into fourAUSP’5 two categories (see Table 0‘15”, The criteria of
`antimicrobial effectiveness for these products are a function of the
`route of administration Wm,
`
`
`
`é:
`
`
`
`
`
`.a....41.1.-a“.mmeteMm-m‘r‘
`
`lE1
`
`%
`
`MEDIA
`
`All media used in the test must be tested for growth promotion. Use
`the microorganisms indicated above under Test Organisms.
`
`PREPARATION OF INOCULUM
`
`Preparatory to the test, inoculate the surface of a suitable volume of
`solid agar medium fiom a recently revived stock culture of each ofthe
`specified microorganisms. The culture conditions for the inoculum
`culture are described in Table 2 in which the suitable media are Soy-
`bean-Casein Digest or Sabouraud Dextrose Agar Medium (see Mi-
`crobial Limits Testing (61))
`To harvest the bacterial and C. albicans cultures, use sterile saline
`TS, washing the surface growth, collecting it in a suitable vessel, and
`adding sufficient sterile saline TS to obtain a microbial count of about
`l X 10“ colony—forming units (cfu) per mL. To harvest the cells of A.
`niger, use sterile saline TS containing 0.05% of polysorbate 80, and
`add sufficient sterile saline TS to obtain a count of about l X 10" cfu
`per mL.
`Alternatively, the stock culture organisms may be grown in a suit-
`able liquid medium (i.e., Soybean-Casein Digest Broth or Sabouraud
`Dextrose Broth) and the cells harvested by centrifugation, then
`washed and resuspended in sterile saline TS to obtain a microbial
`count of about 1 x 10" cfu per mL.
`[NOTE—The estimate of inoculum concentration may be per-
`formed by turbidimetric measurements for the challenge microorgan-
`isms. Refrigerate the suspension if it is not used within 2 hours]
`Determine the number of cfu per mL in each suspension, using the
`conditions of media and microbial recovery incubation times listed in
`Table 2 to confirm the initial cfu per mL estimate. This value serves to
`calibrate the size of inoculum used in the test. The bacterial and yeast
`suspensions are to be used within 24 hours of harvest, but the fungal
`preparation may be stored under refrigeration for up to seven days.
`Change to read:
`
`A
`
`PROCEDURE
`
`mm The test can be conducted eitherin five original contain-
`ers if sufficient volume of productis availablein each container and
`the product container can be entered aseptically (i.e., needle and sy-
`ringe through an elastomeric rubber stopper), or in five sterile, capped
`bacteriological containers of suitable size into which a sufficient vol-
`ume of product has been transferred. Inoculate each container with
`one of the prepared and standardized inoculum, and mix. The volume
`of the suspension inoculum used is between 0.5% and 1.0% of the
`volume of the product. The concentration of test microorganisms that
`is added to theproduct ‘(Categories 1,2 and 3)Aug”, are such that
`the final concentration of the test preparation afier inoculationis be-
`tween 1 X 105 and 1 X 10" cfu per mL of the product. ‘For Category
`4 products (antacids) the final concentration of the test preparation
`after inoculation is between l X 103 and l X 104 cfii per mL of the
`pmduCt- ‘Usrn
`The initial concentration of viable microorganisms in each test
`preparation is estimated based on the concentration of microorgan-
`isms in each of the standardized inoculum as determined by the
`plate-count method.
`Incubate the inoculated containers at 22.5 :t 2.5C. Sample each
`container at the appropriate intervals specified in Table 3. Record any
`changes observed in appearance at these intervals. Determine by the
`plate—count procedure the number of cfu present in each test prepara-
`tion for the applicable intervals (see Procedure under Microbial Limit
`Tests (61)). Incorporate an inactivator (neutralizer) of the specific
`antimicrobial in the plate count or in the appropriate dilution prepared
`for plating. These conditions are determined in the validation study
`for that sample based upon the conditions of media and microbial re-
`covery incubation times listed in Table 2. Using the calculated con-
`centrations of cfii per mL present at the start of the test, calculate the
`change in log“, values of the concentration of cfu per mL for each
`microorganism at the applicable test intervals, and express the
`changes in terms of log reductions.
`A051125
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2020 Page 4
`
`Table l. Compendial Product Categories.
`
`Category
`Product Description
`Ausrzj
`‘1
`Injections, other parenterals including
`emulsions, otic, sterile nasal products, and
`ophthalmic products made with aqueous
`bases or vehicles.
`Topically used products made with aque-
`ous bases or vehicles, nonsterile nasal pro-
`ducts, and emulsions, including those
`applied to mucous membranes.
`Oral products other than antac1ds, ‘Usm
`madepwith aqueous bases or vehicles.
`Antacids made with an aqueous base..A,‘
`(15571
`
`2‘USP25
`
`3AUSP)!
`
`4Ausm
`
`A
`
`A
`
`A
`
`TEST ORGANISMS
`
`Use cultures of the following microorganisms]: Candida albicans
`(ATCC No. 10231), Aspergillus niger (ATCC No. 16404), Escheri-
`chia coli (ATCC N0. 8739), Pseudomonas aeruginosa (ATCC No.
`9027), and Staphylococcus aureus (ATCC No. 6538). The viable mi—
`croorganisms used in the test must not be more than five passages
`removed from the original ATCC culture. For purposes of the test,
`one passage is defined as the transfer of organisms from an estab-
`lished culture to fresh medium. All transfers are counted. In the case
`of organisms maintained by seed lot techniques, each cycle of freez-
`ing, thawing, and revival in fresh medium is taken as one transfer. A
`seed stock technique should be used for long-term storage of cultures.
`Cultures received from the ATCC should be resuscitated according to
`directions. If grown in broth, the cells are pelleted by centrifugation.
`Resuspend in 1/20th the volume of fresh maintenance broth, and add
`an equal volume of 20% (v/v in water) sterile glycerol. Cells grown
`on agar may be scraped from the surface into the 10% glycerol broth.
`Dispense small aliquots of the suspension into sterile vials. Store the
`vials in liquid nitrogen or in a mechanical freezer at no more than -
`50°. When a fresh seed stock vial is required, it may be removed and
`used to inoculate a series of working cultures. These working cultures
`may then be used periodically (each day in the case of bacteria and
`yeast) to start the inoculum culture.
`
`Change to read: Available from American Type Culture Collection,
`10801 University Boulevard, Manassas, VA 20110-2209 (http://
`wwwflatccorg).mum:
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2020 Page 4
`
`

`

`USP 25
`
`Microbiological Tests /’
`
`(55> Biological Indicators—Resistance Performance Tests
`
`1871
`
`
`Table 2. Culture Conditions for Inoculum Preparation
`Inoculum
`Microbial Recovery
`
`Organism
`Suitable Medium
`Incubation Temperature
`Incubation Time
`Incubation Time
`Escherichia coli
`Soybean-Casein
`32.5 :: 2.5”
`18 to 24 hours
`3 to 5 days
`(ATCC No. 8739)
`Digest Broth;
`Soybean-Casein
`Digest Agar
`Soybean-Casein
`Digest Broth;
`Soybean-Casein
`Digest Agar
`Soybean-Casein
`Digest Broth;
`Soybean-Casein
`Digest Agar
`Sabouraud Dextrose
`Agar; Sabouraud
`Dextrose Broth
`3 to 7 days
`6 to 10 days
`22.5 :1: 25°
`Sabouraud Dextrose
`Aspergillus niger
`Agar; Sabouraud
`(ATCC No. 16404)
`Dextrose Broth
`_—_—_———__—_—.__._—._——_——_——
`
`
`
`32.5 : 2.50
`
`18 to 24 hours
`
`3 to 5 days
`
`Pseudomonas aeruginosa
`(ATCC N0. 9027)
`
`Staphylococcus aureus
`(ATCC N0. 6538)
`
`Candida albicans
`(ATCC No. 10231)
`
`32.5 :1: 2.5”
`
`18 to 24 hours
`
`3 to 5 days
`
`22.5 i 2.53
`
`44 to 52 hours
`
`3 to 5 days
`
`CRITERIA FOR ANTIMICROBIAL
`EFFECTIVENESS
`
`The requirements for antimicrobial effectiveness are met if the cri—
`teria specified under Table 3 are met (see Significant Figures and Tol-
`erances under General Notices). No increase is defined as not more
`than 0.5 log10 unit higher than the previous value measured.
`
`Table 3. Criteria for Tested Microorganisms
`
`For Category Al ‘Usm Products
`Bacteria:
`Not less than 1.0 log reduction from the
`initial calculated count at 7 days, not less
`than 3.0 log reduction from the initial
`count at 14 days, and no increase from
`
`the 14 days’ count at 28 days.
`No increase from the initial calculated
`Yeast and Molds:
`
`count at 7, l4, and 28 days.
`
`For Category A2 I mm Products
`Not less than 2.0 log reduction from the
`Bacteria:
`initial count at 14 days, and no increase
`
`from the 14 days’ count at 28 days.
`No increase from the initial calculated
`Yeast and Molds:
`
`count at 14 and 28 days.
`
`For Category ‘3 I my, Products
`Bacteria:
`Not less than 1.0 log reduction from the
`initial count at 14 days, and no increase
`
`from the 14 days’ count at 28 days.
`Yeast and Molds:
`No increase from the initial calculated
`
`count at 14 and 28 days.
`
`For Category ‘4 I um, Products
`No increase from the initial calculated
`Bacteria, Yeast,
`and Molds:
`count at 14 and 28 days.
`
`<55) BIOLOGICAL INDICATORS—
`RESISTANCE PERFORMANCE
`TESTS
`
`Total Viable Spore Count—Remove three specimens of the rele-
`vant biological indicator from their original individual containers.
`Pulp the paper into component fibers by placing the test specimens
`in a sterile 250-mL cup of a suitable blender containing 100 mL of
`chilled sterilized Purified Water and blending for 3 to 5 minutes to
`achieve a homogeneous suspension. Transfer a 10-mL aliquot of
`the suspension to a sterile, screw-capped 16- x 125-mm tube. For
`
`Biological Indicator for Steam Sterilization, Paper Carrier, heat
`the tube containing the suspension in a water bath at 95° to 100°
`for 15 minutes, starting the timing when the temperature reaches
`95°. For Biological Indicatorfor Dry-Heat Sterilization, Paper Car-
`rier, and for Biological Indicator for Ethylene Oxide Sterilization,
`Paper Carrier, heat the tube containing the suspension in a water bath
`at 80° to 85° for 10 minutes, starting the timing when the temperature
`reaches 80”. Cool rapidly in an ice water bath at 0° to 4°. Transfer two
`l-mL aliquots to suitable tubes, and make appropriate serial dilutions
`in sterilized Purified Water, the dilutions being selected as calculated
`to yield preferably 30 to 300 colonies, but not less than 6, on each of a
`pair of plates when treated as described below. Where the biological
`indicator has a low spore concentration, it may be necessary to mod—
`ify the dilution series and to use more plates at each dilution. Prepare
`a separate series of plates for each aliquot. Place 1.0 mL of each se-
`lected dilution in each of two 15— x 100-mm Petri dishes, Within 20
`minutes, add to each plate 20 mL of Soybean-Casein Digest Agar
`Medium (see Microbial Limit Tests
`(61)) that has been melted and
`cooled to 45° to 50°. Swirl to attain a homogeneous suspension,
`and allow to solidify. Incubate the plates in an inverted position at
`55° to 60° for Biological Indicator for Steam Sterilization, Paper
`Carrier, and at 30° to 35° for Biological Indicatorfor Ethylene Oxide
`Sterilization, Paper Carrier, and for Biological Indicator for Dry-
`Heat Sterilization, Paper Carrier, or at the optimal recovery tempera-
`ture specified by the manufacturer, and examine the plates after 24
`and 48 hours, recording for each plate the number of colonies, and
`using the number of colonies after 48 hours to calculate the results.
`Calculate the average number of spores per specimen from the re-
`sults, using the appropriate dilution factor. The test is valid if the
`log number of spores per Carrier at 48 hours is equal to or greater
`than the log number after 24 hours in each case. For Biological Indi-
`catersfor Steam Sterilization, Self-Contained, aseptically remove the
`spore strip from the container, and proceed as directed for Biological
`Indicatorfor Steam Sterilization, Paper Carrier.
`D Value Determination—For all tests described in this section,
`handle each test specimen with aseptic precautions, using sterilized
`equipment where applicable.
`Apparatus—For Biological Indicator for Dry-Heat Sterilization,
`Paper Carrier, use an apparatus of known thermodynamic character-
`istics that has been validated for compliance with the requirements for
`safety1 and performance,2 that consists of a sterilizing chamber
`equipped with a means of heating the contained air, preferably elec-
`trically rather than gas fired, and that has adequate movement of the
`
`' Safety includes design to prevent electric shock or gas exposition and bums,
`where operators can wear protective clothing and gloves against burns from
`touching hot surfaces.
`2 Descriptions ofdifferent types ofdry-heat sterilizing equipment and detailed
`guidelines for determining, monitoring, and controlling the operating para-
`meters have been published by the Health Industry Manufacturers Association
`(HIMA) in Report No. 78—1.7, Operator Trainingfor Dry Heat Sterilizing
`Equipment, and by the Parenteral Drug Association, Inc., (FDA) in Technical
`Report No. 3. Validation ofDry Heal Processes usedfor Sterilization and De-
`pyrogenation.
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2020 Page 5
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2020 Page 5
`
`